Findings

This mutation has been identified in a Swedish family known as Swed2. Originally eight affected individuals were reported over three generations, with memory difficulties beginning at age 47 on average (Clark et al., 1995). A follow-up study described the clinical details of this family in greater depth and published an extended pedigree with 101 individuals over six generations, 18 of whom were affected by dementia. Clinical data were available for 16 of the 18 affected family members and revealed that disease onset in this family was particularly variable, ranging from 44 to 65 years (mean: 54 years, n=16). Variability was also noted in disease duration (five to 23 years) and age at death (55 to 83 years). A commonality among affected individuals was insidious memory loss as the primary presenting feature. Psychiatric problems were also common, and myoclonic jerks and epileptic seizures occurred later in 10 of 16 patients. The mode of inheritance was consistent with autosomal-dominant inheritance in this family; however, one obligate carrier died at age 67 unaffected by dementia. Whether this was due to incomplete penetrance or a very late onset is unknown (Axelman et al., 1998).

Neuropathology

The neuropathology associated with this mutation is unknown. Cerebral glucose metabolism may be affected early, as FDG-PET imaging showed that young, presymptomatic H163Y carriers had decreased glucose metabolism, especially in the thalamus, many years prior to the development of clinical symptoms of AD (Schöll et al., 2011).